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    • In diseased blood vessels increased production of reactive

    2022-08-04

    In diseased blood vessels, increased production of reactive oxygen species (ROS), such as peroxynitrite, superoxide, and hydrogen peroxide, have been found [[53], [54], [55]]. Peroxynitrite was suggested to alter the redox state of sGC [53] while hydrogen peroxide interfered with the action of NO but did not seem to affect the sGC redox equilibrium [55]. Treatment of aging rats with FeTMPyP, a peroxynitrite scavenger, rescued cGMP and phosphorylation of vasodilator-stimulated phosphoprotein (VASP) [56], providing further evidence of NO-sGC-cGMP dysfunction mediated by peroxynitrite. Activating sGC by NO or heme-independent sGC modulator pharmacotherapy also helped attenuate endothelial dysfunction in rat aortas by peroxynitrite [57]. In sGC stimulator, activator, and NO-containing systems, it was found that intracellular superoxide could scavenge NO and shift the sGC redox equilibrium while extracellular superoxide reacted with NO only outside the cell [54]. ROS-mediated shift of the sGC heme redox equilibrium towards the Fe3+ state greatly reduced the activity of the signaling pathway [58]. While many of these studies were conducted in rats [[53], [54], [55]], increased oxidative stress due to a peroxyl radical generator in isolated monkey coronary Annexin V-Cy3 Apoptosis Kit Plus also resulted in a disruption in the sGC redox state, demonstrating the importance of heme regulation in nonhuman primates as well [58]. Heme insertion is a key step for proper maturation and functionality of sGC [59]. Heat shock protein 90 (hsp90) is responsible for heme insertion into sGC by complexing to heme deficient apo-sGC [59]. The heme insertion is driven through the adenosine triphosphatase (ATPase) activity of hsp90, which then dissociates from the fully functional sGC protein [59]. NO stimulates the insertion of heme in apo-sGC-β1, the dissociation of hsp90 from the complex, and the association of sGC-α1 to form the active enzyme [60]. It seems that NO is particularly crucial for the rapid insertion of heme into sGC-β1 and can quickly adjust the equilibrium between apo-sGC-β1 and holo-sGC-β1 [60]. However, how this equilibrium is managed remains to be elucidated [60]. Hsp90 is not required for sGC activation or short-term control of sGC protein levels, but is tonically involved in preventing the degradation of sGC [59,61]. Prolonged inhibition of hsp90 can shunt sGC to proteasomal degradation [59,61]. Heme oxygenase, a key enzyme that converts heme to carbon monoxide (CO) and biliverdin IX, also has some important implications in the alteration and regulation of sGC activity [62]. Genetic deficiency of heme oxygenase-1 (HO-1) in knockout mice led to more severe vascular lesions [63]. In response to various drugs, it was found that HO-1 has an important antioxidant function that assists in maintaining the reduced state of sGC, which is important for normal NO signaling [63]. However, increased HO-1 activity was found to deplete heme, attenuating pulmonary artery relaxation and sGC activity in response to NO [64]. Long-term inhibition of HO-1 with chromium mesoporphyrin effectively restored NO-induced vessel relaxation [64]. These divergent effects seem to indicate a delicate balance in the activity of HO-1 for the proper functioning and signaling of sGC. Similarly, biliverdin IX significantly decreased sGC activity under both basal and NO-stimulated conditions [62]. Bilirubin IX, the reduction product of biliverdin IX that differs by only two hydrogen atoms, demonstrated no effect [62]. With some chemical similarities to heme and other porphyrins, biliverdin IX may have interfered with the activation of sGC by binding to the heme pocket and displacing the heme group [62]. Protoporphyrin IX, the final precursor to heme [65], can endogenously bind and activate sGC [66]. Because of this effect, disruptions in the regulatory mechanisms of heme biosynthesis that allow the accumulation of protoporphyrin could alter the activity of sGC [66]. Angiotensin II could increase mitochondrial superoxide, decreasing ferrochelatase – the enzyme responsible for conversion of protoporphyrin to heme – and depleting sGC [67]. To that end, using a scavenger of mitochondrial superoxide was shown to attenuate the depletion of ferrochelatase and increase vasorelaxation by NO [67]. Essentially, angiotensin II acted as an inhibitor of heme biosynthesis by ferrochelatase, which depleted both heme and sGC levels [67].